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Combined Lenalidomide,Low-Dose Dexamethasone,and Rituximab Achieves Durable Responses in Rituximab-Resistant Indolent and Mantle Cell Lymphomas T ahamtan Ahmadi,MD,PhD1;Elise A.Chong,MD1;Amanda Gordon,BSN,CRNP1;Nicole A.Aqui,MD1;Sunita D.Nasta,MD1;Jakub Svoboda,MD1;Anthony R.Mato,MD,MSCE2;and Stephen J.Schuster,MD1BACKGROUND:Lenalidomide is an immunomodulatory drug with effects on the immune system that may enhance antibody-dependent cell-mediated cytotoxicity and reverse tumor-induced immune suppression.Furthermore,single-agent lenalidomide has therapeutic activity in relapsed/refractory B-cell lymphomas.These immunologic effects potentially may enhance the action of rituxi-mab.METHODS:T o test the efficacy of lenalidomide combined with rituximab,the authors conducted a phase2trial of lenalidomide, low-dose dexamethasone,and rituximab in patients who had rituximab-resistant,relapsed/refractory,indolent B-cell or mantle cell lymphomas.Patients received two28-day treatment cycles of lenalidomide10mg daily and dexamethasone8mg once weekly(partI).During cycle3,4weekly doses of rituximab375mg/m2were administered with lenalidomide-dexamethasone(part II).After thepart II response assessment,stable or responding patients continued to receive lenalidomide-dexamethasone.RESULTS:Twenty-seven patients with follicular(n518),mantle cell(n55),small lymphocytic(n53),and marginal zone(n51)lymphomas started ther-apy;3of27patients discontinued therapy because of adverse events and were not evaluable for response.For24patients,the over-all response rate after part I was29%(4patients had a complete response[CR]or CR unconfirmed,and3patients had a partial response),and the overall response rate after part II was58%(8patients had a CR,and6patients had a partial response).For27 patients,at a median follow-up of12.2months,the median progression-free survival was23.7months.CONCLUSIONS:The combina-tion of lenalidomide,low-dose dexamethasone,and rituximab achieved high response rates with durable responses in patients with rituximab-resistant,indolent B-cell and mantle cell lymphomas.Overall response rate increased from29%after two28-day cycles of lenalidomide and low-dose dexamethasone to58%after the addition of rituximab,suggesting that lenalidomide can overcome resist-ance to rituximab.Cancer2014;120:222–8.V C2013American Cancer Society.KEYWORDS:non-Hodgkin lymphoma,lymphoma,low-grade,lenalidomide,rituximab,follicular lymphoma,immunomodulation,immu-nomodulatory therapy.INTRODUCTIONThe addition of rituximab to chemotherapy improves clinical outcomes for patients with low-grade B-cell lymphomas, and the inclusion of rituximab in treatment regimens is considered the standard of care for B-cell non-Hodgkin lympho-mas.1,2Unfortunately,many patients who receive rituximab-chemotherapy or rituximab monotherapy eventually relapse and develop resistance to rituximab or to rituximab-containing combination therapies.In our experience,the5-year over-all survival(OS)for patients with low-grade follicular lymphoma who fail to respond to or develop resistance to rituximab or a rituximab-containing treatment regimen is58%,3which is markedly decreased compared with the reported survival for all patients with follicular lymphoma.4Thus,there is considerable incentive to overcome resistance to rituximab.Lenalidomide is an immunomodulatory drug with effects on the immune system that may enhance antibody-dependent cell-mediated cytotoxicity and reverse tumor-induced immune suppression.5,6These immunologic effects could potentially enhance the action of rituximab.Furthermore,single-agent lenalidomide has demonstrated therapeutic activity in relapsed or refractory B-cell lymphomas,7,8including follicular lymphoma and mantle cell lymphoma.9,10 Corresponding author:Stephen J.Schuster,MD,Perelman Center for Advanced Medicine,2West Pavilion,Room2-393S,3400Civic Center Boulevard,Philadel-phia,PA19104;Fax:(215)662-4064;stephen.schuster@1Lymphoma Program,Abramson Cancer Center of the University of Pennsylvania,Philadelphia,Pennsylvania;2Chronic Lymphocytic Leukemia Program,John The-urer Cancer Center,Hackensack University Medical Center,Hackensack,New Jersey.The first two authors contributed equally to this work.The authors thank Frannie and Jim Maguire and Margarita Louis-Dreyfus for their support of the Lymphoma Program at the Abramson Cancer Center of the Uni-versity of Pennsylvania.DOI:10.1002/cncr.28405,Received:July8,2013;Revised:August11,2013;Accepted:August26,2013,Published online October7,2013in Wiley Online Library()Preclinical studies have demonstrated the potential for synergy between lenalidomide and rituximab,both in vitro and in murine B-cell lymphoma models.5,11–13In vitro,after pretreatment with lenalidomide,rituximab produced more growth inhibition11and greater apoptosis compared with rituximab alone.11,12This combination also demonstrably enhanced the natural killer cell, antibody-dependent cellular cytotoxicity of rituximab.12,13 To test the efficacy of lenalidomide combined with rituximab,we conducted a phase2clinical trial in patients with indolent B-cell or mantle cell lymphomas who were previously resistant or refractory to rituximab or rituximab-based therapy.Low-dose,weekly dexametha-sone was added to the regimen based on anecdotal clinical experience suggesting the amelioration of lenalidomide side effects,especially rash and tumor flare,as well as the known synergy between corticosteroids and immunomo-dulatory drugs.14MATERIALS AND METHODSThis was a single-center,prospective,open-label,phase2 study examining the combination of lenalidomide,low-dose dexamethasone,and rituximab in patients with previously treated,rituximab-refractory or resistant,in-dolent B-cell or mantle cell lymphomas.The study was conducted in accordance with the Declaration of Helsinki and was approved by the institutional review board of the University of Pennsylvania.All patients provided written informed consent before study entry.The clinical trial registration number was NCT00783367(available at:)under the approved registry name“Combination Therapy Using Lenalidomide(Revlimid)–Low-Dose Dexamethasone and Rituximab for Treatment of Rituximab-Resistant, Nonaggressive B-Cell Lymphomas.”Adults(aged 18years)with histologically con-firmed,CD20antigen-expressing follicular(grades1,2, and3a),marginal zone,small lymphocytic,lymphoplas-macytic,or mantle cell lymphomas were eligible.Tissue blocks were reviewed to confirm each diagnosis using the 2008World Health Organization classification criteria.15 Patients were required to have progressive lymphoma requiring therapy,a life expectancy>3months,and at least1measurable lesion( 2cm in greatest dimension). The criteria to initiate treatment on protocol required patients to have refractory or progressive lymphoma (defined as new lesions or enlargement 50%of existing lesions)within6months of rituximab monotherapy or a rituximab-chemotherapy combination.All images and response assessments were reviewed by the principal inves-tigator and a board-certified radiologist.Patients were withdrawn from the study if they experienced relapse or disease progression after having received rituximab or at the discretion of the treating physician or patient.In part I of protocol therapy,patients received oral lenalidomide10mg daily and oral dexamethasone8mg once weekly for two28-day cycles.Response evaluation (computed tomography[CT]or positron emission to-mography/CT imaging)was performed at the end of the second cycle(part I response).Patients then initiated part II of protocol therapy—cycles3through5—regardless of their response status after part I.During cycle3,in addi-tion to continuous daily lenalidomide and weekly dexa-methasone,patients received rituximab375mg/m2once weekly for4weeks.Radiologic response was reassessed2 months after completing rituximab at the end of cycle5 (part II response).Patients who demonstrated either a response or stable disease were permitted to continue receiving lenalidomide with or without dexamethasone until they developed disease progression or withdrew,but patients were not permitted to receive additional rituxi-mab while on study(Fig.1).Patients who continued receiving lenalidomide had CT or PET/CT imaging at12 months,18months,and24months after enrollment and then yearly for a maximum of5years from study entry. Lenalidomide was held for toxicity grade 3based on ver-sion3of the National Cancer Institute Common Termi-nology Criteria for Adverse Events,and it was restarted at a lower dose(either5mg daily or every other day)upon the resolution of toxicity( grade2)within28days.At the discretion of the treating physician,the dose of oral lenalidomide could also be decreased to5mg daily or5 mg every other day for lower grade symptoms possibly related to lenalidomide.All patients received either aspirin 81mg daily or warfarin for antithrombotic prophylaxis. Contraceptive counseling was performed according to the RevAssist program(Celgene Corporation,Summit,NJ).The primary study endpoint was the overall response rate(ORR)after cycle5(part II response)using interna-tional workshop response criteria for non-Hodgkin lym-phoma.16For25evaluable patients,using an a value of .05,we estimated80%power to detect an ORR of at least 50%.Secondary clinical endpoints included progression-free survival(PFS),16response duration(RD)16/time to progression(TTP),17OS,16and a detailed toxicity assess-ment using version3of the National Cancer Institute Common Terminology Criteria for Adverse Events.The Kaplan-Meier method was used to estimate PFS,RD/TTP, and OS.Statistical analyses were performed using STATA version9.2(Stata Corporation,College Station,Tex).RESULTSPatient CharacteristicsTwenty-seven patients were enrolled between July 2008and May 2010.Prior to enrollment,19patients had dis-ease progression after or during rituximab,6patients had stable disease after rituximab,and 2patients relapsed within 6months of responding to rituximab.The median time from diagnosis was 6.77years (range,0.89-26.12years).Additional characteristics of the study cohort at enrollment are presented in Table 1.Response Assessment and Survival AnalysisFor any patient who received at least 1dose of lenalido-mide (N 527),the ORR after part I was 26%,and the ORR after part II for all 27patients who started protocol therapy,even if they did not receive rituximab,was 52%.There was no difference in the response rate between patients whose rituximab resistance-defining therapy was a rituximab-chemotherapy combination,rituximab monotherapy,or rituximab maintenance (P 5.4).Twenty-four of 27patients received rituximab dur-ing cycle 3and were evaluable for response to part I (2cycles of lenalidomide and low-dose dexamethasone)and part 2(lenalidomide and low-dose dexamethasone incycles 3-5with rituximab during cycle 3).After part I,the ORR for these 24patients was 29%(complete response [CR]/CR unconfirmed [CRu]rate,17%);the ORRs were 20%for follicular lymphoma (3of 15patients),60%for mantle cell lymphoma (3of 5patients),33%for small lymphocytic lymphoma (1of 3patients),and 0%for marginal zone lymphoma (0of 1patient).After part II,the ORR for these 24patients was 58%(CR rate,33%);the ORRs were 53%for follicular lymphoma (8of 15patients),60%for mantle cell lymphoma (3of 5patients),67%for small lymphocytic lymphoma (2of 3patients),and 100%for marginal zone lymphoma (1of 1patient).Nine of 24patients (38%)demonstrated an improvement in protocol-defined response after receiving rituximab.Nineteen of 24patients (75%)continued to receive lenali-domide and weekly dexamethasone after the completion of cycle 5.Of 14patients who had stable disease or a par-tial response (PR)after completing 4weekly doses of rit-uximab (part II response assessment),only 1patient had a further improvement in response status during follow-up.As of November 10,2012,the median follow-up was 12.2months (range,0.9-52.7months),and the estimatedTABLE 1.Patient CharacteristicsCharacteristicNo.of Patients/Total No.(%)Sex Men 15(55.5)Women12(44.5)Age:Median [range],y 60[35-85]Bulky adenopathy, 5cm 10/27(37)HistologyFollicular lymphoma,grade 1or 218/27(66)Mantle cell lymphoma5/27(19)Small lymphocytic lymphoma 3/27(11)Marginal zone lymphoma 1/27(4)Bone marrow involvement 5/27(18.5)Elevated LDH6/27(22.2)No.of prior therapies:Median [range]3[1-7]Underwent prior autologous stem cell transplantation 3/27(11.1)ECOG performance status 0-126/27(96)21/27(4)Regimen-defining rituximab resistance Rituximab maintenance 10Rituximab monotherapy 10Rituximab-CHOP2Rituximab-ibritumomab tiuxetan 1Rituximab-ICE1Rituximab-hyper CVAD 1Rituximab-gemcitabine 1Rituximab-epratuzumab1Abbreviations:CHOP ,cyclophosphamide,vincristine,doxorubicin,and prednisone;hyper CVAD,cyclophosphamide,vincristine,doxorubicin,and dexamethasone alternating with high-dose methotrexate and high-dose cytarabine;ECOG,Eastern Cooperative Oncology Group;ICE,ifosfamide,carboplatin,and etoposide;LDH,lactatedehydrogenase.Figure 1.The protocol schema is illustrated.Each cycle was 28days in duration.median PFS and OS were 23.7months and not reached,respectively (Fig.2A).The RD/TTP for responding patients was 26.6months (Fig.2B).The percentage change in the sum of the products of the maximum per-pendicular,cross-sectional dimensions of target lesions in individual patients after part I (lenalidomide-dexametha-sone)and part II (lenalidomide-dexamethasone-rituxi-mab)are illustrated shown in Figure 3A through C.SafetyThe most common adverse event attributed to lenalido-mide was a mild change in bowel habits,usually increased frequency,which did not warrant discontinuation of ther-apy (grade 1).The reported grade 3or 4treatment-related adverse events were neutropenia (8of 27patients;30%),leukopenia (4of 27patients;15%),hypokalemia (4of 27patients;15%),anemia (2of 27patients;7%),hypophos-phatemia (2of 27patients;7%),thrombocytopenia (2of 27patients;7%),transaminase elevation (1of 27patients;4%),pneumonia (1of 27patients;4%),diarrhea (1of 27patients;4%),fatigue (1of 27patients;4%),rash (1of 27patients;4%),tumor flare (1of 27patients;4%),pulmo-nary embolism (1of 27patients;4%),and hyperuricemia (1of 27patients;4%).Four patients (15%)had adverse events that led to discontinuation of therapy,including 3who discontinued before part I response assessment (myo-carditis,rash,thrombocytopenia)and 1patient who dis-continued after the part II response assessment (second malignancy).Four patients (15%)had treatment inter-ruptions and dose reductions secondary to toxicity (thrombocytopenia,transaminase elevation,neutropenia,and tumor flare).One death from myocarditis occurred shortly after initiation of lenalidomide,low-dose dexamethasone.18DISCUSSIONIn this study,patients with indolent B-cell or mantle cell lymphomas who were previously resistant to rituximab-based therapy received combined lenalidomide,low-dose dexamethasone,and rituximab.The ORR and the CR rate,as well as the TTP,were superior to the results reported for retreatment with single-agent rituximab in patients who were not selected for rituximab resistance.17Although the ORR increased from 29%after 2cycles of lenalidomide plus low-dose dexamethasone to 58%after the addition of rituximab,based on the design of this single-arm trial,it was not possible to determine with certainty whether rituximab improved what would have been the response to further continuation of lenali-domide plus low-dose dexamethasone alone.However,of 20patients who ultimately had reductions in tumor vol-ume on this regimen,7patients initially had increases in their tumor volumes before the addition of rituximab (Fig.3A).This suggests a response to rituximab in these patients.In addition,of the other 13patients who ulti-mately had a reduction in tumor volume on this regimen,12had further reductions in tumor volume after receiving rituximab,which also suggests enhanced efficacy for the rituximab combination over lenalidomide plus low-dose dexamethasone alone (Fig.3A).Although a few patients had CRs after receiving lenalidomide alone,both the tim-ing and the magnitude of responses after the addition of rituximab in these previously rituximab-resistantpatientsFigure 2.Progression-free survival and response duration are illustrated.(A)This Kaplan-Meier curve illustrates progression-free survival for all enrolled patients (n 527).(B)This Kaplan-Meier curve illustrates response duration (or time to progression as defined by Davis et al 17)for all responding patients measured from the first observation of response (CR,CRu,or PR)after either part I or part II of treatment until progression (n 514).suggest that the addition of rituximab to lenalidomide improved responses over lenalidomide plus low-dose dexamethasone alone.To our,knowledge,this study is the first to describe the efficacy of combination lenalidomide,low-dose dexa-methasone,and rituximab both in patients who were uni-formly documented as resistant to rituximab and in patients with low-grade follicular lymphoma.Rituximabis a cornerstone of treatment for low-grade follicular lym-phoma,and patients with rituximab-refractory,low-grade follicular lymphoma have poorer OS compared with all patients diagnosed with follicular lymphoma.3,4Treat-ment with lenalidomide plus rituximab appears to be well tolerated and effective in patients with indolent B-cell and mantle cell lymphomas and may offer another therapeutic option for previously treated patients who have apoorFigure 3.Percentage changes in tumor measurements are illustrated for (A)all evaluable patients (n 524),(B)all evaluable patients with follicular lymphoma (n 515),and (C)all evaluable patients with mantle cell lymphoma (n 55).Asterisks in A indi-cate patients who were continuing therapy.prognosis.Lenalidomide also has the advantage of being an oral formulation.In addition,lenalidomide can be continued for years in the absence of cytopenias;the lon-gest patient we report on has received lenalidomide for over4years.Moreover,in our experience,combination lenalidomide plus low-dose dexamethasone and rituxi-mab did not interfere with the ability to administer subse-quent chemotherapy.The combination of lenalidomide and rituximab reportedly is effective in relapsed or refractory,aggressive B-cell lymphomas,including mantle cell lymphoma (ORR,57%)19;relapsed or refractory diffuse large B-cell, follicular grade3,and transformed lymphomas(ORR, 33%)20;and de novo diffuse large B-cell lymphoma (ORR,35%).21These trials differ from our study,in that they used a different dose and schedule of lenalidomide (oral lenalidomide20mg daily on days1-21of a28-day cycle19–21)as well as different schedules for rituximab administration(rituximab weekly for cycle119,20or ritux-imab every other week for4cycles21);thus,those response rates are not directly comparable to our results.In conclusion,we report the first clinical trial of combined lenalidomide,low-dose dexamethasone,and rituximab in patients with rituximab-resistant,indolent B-cell lymphoma or mantle cell lymphoma.Our data sup-port other reports of efficacy for rituximab-lenalidomide in relapsed19–23and previously untreated,indolent B-cell lymphoma24and,in part,are the basis for an ongoing multicenter,randomized trial comparing lenalidomide-rituximab with rituximab-chemotherapy as first-line ther-apy of follicular lymphoma(NCT01476787). FUNDING SUPPORTTahamtan Ahmadi received a grant from the Leukemia and Lym-phoma Society for the conduct of this study.Stephen J.Schuster and Nicole A.Aqui received research support from Celgene Corpo-ration for this clinical trial.CONFLICT OF INTEREST DISCLOSURES Jakub Svoboda received a grant from Celgene Corporation for an investigator-initiated clinical trial.Anthony R.Mato has received compensation as a member of the Speakers Bureau of Celgene Corporation.REFERENCES1.Marcus R,Imrie K,Belch A,et al.CVP chemotherapy plus rituxi-mab compared with CVP as first-line treatment for advanced follicu-lar lymphoma.Blood.2005;105:1417-1423.2.Hochster H,Weller E,Gascoyne RD,et al.Maintenance rituximabafter cyclophosphamide,vincristine,and prednisone prolongs progression-free survival in advanced indolent lymphoma:results of the randomized phase III ECOG1496study.J Clin Oncol.2009;27: 1607-1614.3.Abdollahi S,Chong EA,Olin RL,et al.The impact of rituximab re-sistance on overall survival rate in 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